Sustained release type of pharmaceutical vehicles



United States This invention relates to a sustained release type ofpharmaceutical vehicle and to the method of its preparation. Moreparticularly, the invention concerns a novel and more efficient sealcoating to be employed in the preparation of medicinal carriers withinsaid pharmaceutical vehicle, said vehicle including the carrier insuitable dosage amount and form, as well as forms of tablets, capsulesor pellets.

Multicoated sustained release or delayed action type pharmaceuticaltablets are known, and one type of such tablet and the method of itsmanufacture has been described, for example, in US. Patent 2,853,420.The tablet described in that patent is built up by applying to a centralcore or basic pellet of compressed sugar or corn starch a multiplicityof medicating impregnation layers in a series of successive coatingsteps. When perhaps 12 medicating coatings have been thus applied,thereby increasing the weight of the core by about 0.75%, the core orpellet as medicated is then successively coated with from 25 to 250coatings of a sustained or delayed action material, the thickness of thecoatings being gauged so as to provide a sustaining factor ofapproximately one hour for each 25 coatings. This will increase theweight of the tablets another 1.5%. Thereafter, one-tenth of the coatedpellets are removed, and the remaining nine-tenths coated with another25 layers of coating, yielding a product having a sustaining factor of 2hours. If desired, oneninth of the latter batch can be separated and theremaining eight-ninths coated with another 25 layers to achieve asustaining factor of 3 hours therefor, and so on. Thus even a 250-layercoated tablet can be built having a sustained action for about hours.The object was to produce a tablet which will postpone or delay actionfor a period of several hours during which the tablet passes through thestomach into the intestines, and then assure liberation of the medicantfor a period of several hours in the intestinal tract.

To achieve the impregnation of the core with medicament, and to applythe successive coating layers, the aforenentioned patent employs acoating composition comprising a solution in 85% alcohol or inchloroform of an ether or ester of cellulose, such as for example, ofmethylcellulose, ethylcellulose, or cellulose acetate-phthalate. About10% of beeswax and castor oil is added to promote plasticity andelasticity of the resulting coating. Preferably the coating operation isperformed in a rotating pan, a layer of fine talc being applied to eachbatch while the coating is still soft. Preferably the coating issubstantially neutral. A suflicient number of coatings is thus providedto insure predetermined delaying or sustaining action even if individualcoatings are imperfect or not homogeneous. The coatings graduallydecrease in thickness as they progress from the core in proportion toits distance from the center, and being generally not more than about 1%of this distance.

It is also known to employ as an enteric coating composition, soluble inthe intestinal tract and not in the gastric fluids, an inner coating ofcellulose acetate-phthalate and an outer coating of beeswax, as acombined coating on a tablet. Conversely, the wax may serve as the innercoating and the cellulose acetate-phthalate as the outer coating. Ineither case, the combination acts to prevent attack on the medicament inthe stomach. However, when the coating is penetrated, there occurs atotal release of the medicament. These coatings were applied in theprior art in an amount as much as 8% by weight of the tablet.

Experience has shown that in multicoated tablets of the characterdescribed, a sustained release factor based upon number of coatinglayers per se is not always reliable. Moreover, the celluloseacetate-phthalate-beeswax combination type of coating as presently usedin multicoated tablets is ineflicient in that an extremely large numberof coatings is required, with resultant expensive and cumbersomeprocessing of the tablets in the course of manufacture.

It is also known to prepare sustained release powders by applying to apowdered medicament a first coating of a fatty material such as a fattyalcohol, a glyceride, or beeswax in an amount ranging from 25% to byweight of the powder, the fatty material being in solution in an organicsolvent such as alcohol or chloroform. A secondary coating of the samematerial or materials may also be applied.

In accordance with the present invention, it has been found that by acareful selection of coating ingredients, and the combination of theseingredients into a particularly useful mixture, the emphasis in coatingcan be shifted from number of coatings to a percentage increase inweight of the carrier to be coated. Furthermore, in accordance with theinvention, the rate of hourly release can be predicated upon such weightincrease and not upon multiplicity of coatings, introducing a newconcept in this field. This novel concept makes possible the productionnot only of carriers containing a single active ingredient ormedicament, but also of carriers containing two or more medicaments,including incompatibles. It permits the liberation of predeterminedamounts of medicament from coated granules which have been preparedeither with a single coated medicament surrounding the central core orpellet, or with additional layers of coated medicament, with successiverelease of the medicaments, which may be additive, synergistic, orantagonistic, after a time lapse, and with no danger of theeirinteraction or lessening of their activity in the system of the patient.

In the preparation of the carriers, there is employed as a central core,pellet or granule, a mixture of cane sugar and corn starch, or wheat orpotato or rice starch. The mixture is finely ground and worked intoapproximately round granules in a rotating pan in conventional manner toproduce granules or basic pellets having a mesh size between about 10and 20 mesh. Small pellets of the active medicament may also beformulated as a core. Thus, a given amount of medicament may be coatedby spraying with a saturated solution of sucrose, or with a solution ofcellulose acetate-phthalate, or with a solution of a pharmaceuticalglaze or of a vegetable gum, and then tumbled in a rotating pan whiledrying with a blast of cool air, followed by screening to 10 to 20 meshsize.

The core pellets are placed in a rotating pan and are subjected totreatment with a solution of an adhesive material in a volatile organicsolvent in an amount sufficient to cover the surface of each pellet.There may be employed for this purpose any of the conventionally employed adhesives or exci-pients, such as cellulose acetate phthalate orshellac. The volatile solvent may be any solvent which evaporatesrapidly leaving no toxic residue, for example, alcohol, ether, acetone,or chloroform. When the surface of the pellets has become tacky owing toevaporation of the solvent, there is added an amount of activeingredient or medicament in the form of a fine powder, sufficient toevenly coat and adhere to the pellet surfaces. This process is continueduntil the requisite dosage amount of the medicament has been impregnatedevenly on the surface of each pellet. Any desired type of medicament maybe thus applied, including, for example, =sympathomimetic agents, suchas amphetamine or isoproterenol (Isopropyl-Arterenol), anti-biotics,vitamins, minerals, drugs, cardiac agents, barbiturates, and the like.The total weight of medicament employed may approxi- 5 mate the totalweight of pellets to be coated. Thus, where a single medicament isapplied, it will be used in an amount about equal to the weight ofpellets. If several drugs are applied, the total weight of the drugswill approximate the total weight of the pellets. The coating operationcan be carried out in any conventional type of equipment, such as, forexample, a 36 inch diameter coating pan of the rotating type, operating,for example, at a speed of about 30 r.p.m. The pan is provided withmeans for admitting a flow of heating or cooling air to its interior.Where the core pellet is a medicament, some of the foregoing steps canbe eliminated.

A pellet, prepared as described, and with no additional coating, will,upon oral administration, provide immediate release of the medicamentinto the stomach of the patient. If desired, however, an entericcoating, such as a solution of cellulose acetate-phth-alate inchloroform may be applied to provide a glaze protective coating on thepellet which is unafiected by stomach juices, but which will dissolve inthe alkaline intestinal fluids, releasing the medicament in theintestinal tract. If the cellulose acetate-phthal-ate solution isapplied to the medicament-impregnated pellets in an amount ofapproximately 2 pints per 50 lbs. of pellets, a coating is producedwhich will withstand the action of the stomach juices for ap proximatelyone hour, thus providing sufficient time for average passage of thecarrier into the intestinal tract.

It is frequently necessary in medication to delay the release of drugsfor considerably more than the one hour period provided by the foregoingtype of carrier. In such a case the problem becomes one of providing apellet with a coating or several coatings of a retardant material in anamount suflicient to delay exposure of the medicament to the intestinalfluids for periods of 2 to hours, or more. Moreover, it is oftendesirable to allow larger dosages to be released at a slower rate, Whileat the same time controlling the rate of release so that no more than adefinite predetermined proportion of the dosage is released in a givennumber of hours. It may also be desirable to provide means whereby twoor more drugs can be released in succession at such time intervals thatthey will not interfere in their therapeutic action. The successivelyreleased drugs may be such that the second may either offset orsupplement the first released drug, for example a vasodilator and avasoconstrictor, or a soporiiic and a stimulant.

These objectives are achieved by the novel coating composition andmethod of the present invention.

In accordance with the present invention there is provided a novelcoating composition which is substantially unaifected by the stomachjuices, and whichvretards the action of the intestinal fluids. The novelcoating composition is thus enteric in character, but by reason of aslight degree of acidity it serves to neutralize the alkaline intestinalfluid and hence to delay its action on the coat ing. Moreover, theingredients of the coating impart to the coating a melting point higherthan body temperature (98 PR), thereby further providing a retarding o1delaying action to the effect of the intestinal fluid.

It has been found that the application of the novel coating compositionto the core pellet may be regulated so to produce a total increase inweight of the pellet which will result in retardant effect with respectto the intestinal fluid action of approximately one hour. The actualweight increase imparted to the pellet is governed by the known rate ofabsorption of the medicament to be released in the intestinal tract.Thus, in the case of a slowly absorbedmaterial the Weight increase of agiven oa g h d be of the order of magnitude of about 75 5%. In the caseof a rapidly absorbed material, the weight increase may be of the orderof about 10%. However, for achieving a retardant factor of one hour, ithas been found that an average weight increase of from about 7% to about8%, or approximately 7.5% is generally desirable. Each such increase inweight of the pellet of 7.5% provides an additional hour of retardationin the intestinal tract, so that by applying a succession of coatingseach representing 7.5 by weight, delays of 2 to 10 or more hours mayreadily be attained. If a single drug is applied to the core pellet, theentire amount may be released after a predetermined time of say 4 hours.If the drug layers are divided into two or more portions, a part may bereleased in 1 hour and the remainder, for example, at any other desiredintervals. The same is true if two or more different drugs are employedin a single carrier.

The novel coating composition of this invention, which is only slowlyaffected by the intestinal fluids, comprises a mixture of not less thanabout by weight of a glyceride and minor amounts of at least one fattyalcohol and of beeswax. Thus, the glyceride will generally range betweenabout 95 and 99% by weight of the mixture, the fatty alcohol weightbetween about 0.1% and 0.3%, and the beeswax weight about 0.01% and0.05%. The respective ingredients are dissolved in a suitable organicvolatile solvent and maintained at a temperature suflicient to keep theingredients in solution.

The glyceride may be any suitable glyceryl ester of a fatty acid or ahydrogenated aliphatic acid, such as, for example, glycerylmonostearate, glyceryl distearate or glyceryl ester of hydrogenatedcastor oil, but glyceryl monostearate is preferred. The fatty alcohol isany suitable long-chain alcohol, such as cetyl, myristyl, or stearylalcohol. The beeswax is a purified grade, such as white bleachedbeeswax.

The proportions of these ingredients are correlated with the speed ofabsorption of the medicament, and with the final weight of the carrier.Thus, if the final weight of the carrier is between 300 and 600 mg, apreferred coating composition in accordance with the invention wouldcomprise:

Weight per Ingredient: carrier, milligram Glyceryl monostearate 45-55Cetyl alcohol 0.25-0.75 Myristyl alcohol 0.25-0.75 Bleached whitebeeswax 0.005-0.24

However, if a slowly absorbed medicament is used, the

following coating composition would also give satisfactory results:

Weight per Ingredient: carrier, milligram Glycerol ester of hydrogenatedcastor oil 65-70 Cetyl alcohol 0.25-0.75

Myristyl alcohol 0.1-0.5

Bleached white beeswax 0.15-0.25

EXAMPLE 1 A tablet containing 250,000 units of penicillin (for examplein the form of benzylpenicillin sodium) is manufactured by treating aweighed amount of basic pellets with an adhesive solution having thecomposition:

6 completed, the 160 lbs. total of portions 3 to 10 inclusive will haveincreased in weight by approximately 64 lbs., yielding a total weight ofapproximately 224 lbs. Portion It will be seen from Table 1 that,starting with 200 lbs., the A and portions each weigh 20 lbs. and areset aside, leaving 160 lbs. of medicated pellets which are to be treatedwith the wax solution. When this treatment is 75 5322 22acetate'phthalate i 33: 2 is now blended in and the combined portions2-10 are 0 p 5 treated with 1 gallon of cellulose acetate-phthalatesoluand impregnating said pellets with layers of the penicillin tion,yielding at this point a total weight of 224 lbs. plus medicament untila predetermined amount of the medica- 20 lbs. of portion 2, plus 1 lb.of cellulose acetate-phthalate ment has been evenly placed upon eachpellet surface. contained in the 1 gallon of its solution, or a total of245 Thus, 99 lbs. of pellets are combined with 99 lbs. of lbs. The firstportion removed, or 20 lbs., and not further penicillin by the use of 2gallons of the above adhesive treated, is now added, making a total of265 lbs. of solution, containing 2 lbs of solids, thus yielding a totalcompleted pellets, which can be used as such, or further Weight oftreated and coated pellets of 200 lbs. The converted into tablets orcapsules as desired. Thus, in acetone evaporates, leaving the celluloseacetate-phthalate accordance with this procedure, portions 2-10 arefurther on the pellet surfaces. A one-tenth portion (#1) by treated withcellulose acetate-phthalate solution only after Weight of themedicinally treated batch is removed and the application of the waxsolution to portions 3-10 is set aside, pending additional treatment ofthe remaining completed. The amount of cellulose acetate-phthalateellets. Another portion (#2) totaling by weight the solution used forthe application of finishing coatings on balance of the medicatedpellets is also removed and set portions 2-l0 is 1 gallon, therebyadding but 1 lb. to the aside. The remaining weighed medicinally treatedpellets overall weight of the treated pellets. For conversion into arefurther treated with a solution of wax-like texture as tablets, selectedportions or all portions together may be described previously, until theweight has been increased mixed with suitable amounts of filler, binder,and lubriby 7.5%. When completed, a /a portion (#3) of the cants andcompressed into tablet shapes. medicinally treated Wax-like coveredpellets is removed Upon ingestion, the tablet will disintegrate andrelease and set aside. Further additional processing with the theentrapped pellets. Pellets of portions #1 will release wax-like coatingsolution is continued and applied to the penicillin immediately uponingestion. Pellets within the remainder of the batch until each achievesanother 7.5% tablet f portions #2 through #10 will travel through theweight increase. The wax solution employed has the stomach (gastricmedia contact) without any noticeable composition: change until enteringthe intestinal tract, whereupon pellets v E from portions #2 through #10will dissolve their surface Gbceryl monostearate 900 coatings (celluloseacetate-phthalate and acetone) and Cetyl alcohol do 25 0 th rk alviyristyl alcohol d0 25 exp Se elf Wax 1 e Bleached White beeswax do 10The pellets from portion #2 Wlll expose the pen1c1ll1n chloroform 1 forabsorption having no wax-like resistance against alkali (intestinalmedia) as have pellets #3 through #10. The waxy ingredients aredissolved in the chloroform and During further stages of the digestiveprocess, pellets maintained at a temperature between 65 and 67 C. from#3 portion will release penicillin for absorption with- When themedicament has a slow rate of absorption, a in the next hour, and eachsucceeding hour of digestive wax solution may be employed which has thecomposiprocess Will further break down the wax-like coating tion:substances and allow the penicillin to be released in ac- Glycerol esterof hydrogenated castor oil grams 900 40 Egg??? g i d gi i i i of wax"hkematenal Cetyl 31501101 d6 25 P ac P6 Myristyl alcohol do 25 EXAMPLE 2 fiWhite beeswax g; Utilizing the method as described in Example 1, two

0m medicaments may be incorporated into the pellet struc- Portions ofweighed amounts totaling /6, A, ture. Medicaments usually antagonisticto one another /5, V2 (one-half) and balance are removed upon comcan becommonly used and incorporated into an overall pletion of each 7.5%increase in weight over the prevehlcle, be it tablet, capsule 0r p p rviously removed portion. After coating the basic pellet with amedicament such The sequence of steps is summarized in the following asdextro-amphetamine sulfate, the medicated pellets are I T bl 1; treatedwith the wax-like coating solutions to sustain Table 1 SCHEDULE FORTREATMENT OF PELLETS Addition of Pellets removed Weight in Coatings Ifrom Pan Weight Portion lbs., Start Weight 1.11 pounds No. of each afterremainstep Percent Weight Coating Propor- Weightin ingiu Weight in tionlbs. pan Increase Pounds 1/10 20.0 180.0 1/9 20.0 160.0 7. 5 1/8 1 21.50150. 50 7.5 1/7 23.1125 138.6750 7.5 1/6 24.8459 124.2297 7.5 1/526.7094 106. 8375 7.5 1/4 28. 7128 86.1377 7.5 1/3 30. 8660 61.7320 7.51/2 33.1810 33.1809 7. 5 All 1 35. 6695 Portions 2-10 to be treatedfurther after blending. Weight of portions 2-10 will be activity afteringestion, for a predetermined time. Each hourly determination isaccomplished by every 7.5% increase in weight of wax-like coatings addedto the pellets.

In the case of an eight-hour sustaining factor, the

7, amount of wax-like coatings applied would result in a weight increaseof 60%. In the case of a four-hour sustaining factor, the amount ofwax-coatings applied would show a resultant increase in weight of 30%over the original medicated pellets.

When intestinal time factor is achieved, several coatings of OAR-acetonesolution are applied over the waxcovered pellets and the secondmedicament is applied to the pellet surface (phenobarbital or other typesedative). The pellets are dried prior to being placed into vehicle ofchoice.

Upon ingestion, be it tablet, capsule or pellet, per se, the lattermedicament would be released immediately (phenobarbital or other typesedative) and upon the pellets exposing the C.A.P.-acetone coating inthe stomach, no noticeable change would occur until the pellets reachthe intestinal tract.

The C.A.P.-acetone coating dissolves when in contact with intestinalfluids (alkali) and exposes its wax-like coating, which will dissolve inaccordance with the hourly factor given same by the 7.5% series ofWax-like coating increases.

When proper time interval is reached the existing pellets will releasethe former medicament (dextro-amphetamine sulfate) and the resultanttherapeutic activity will take place, this activity being antagonisticto the activity caused by the first medicament released.

This process may be reversed and time interval of antagonistic activitycan be controlled in accordance with the amounts of series of wax-likecoatings utilized in the pellet treatment.

EXAMPLE 3 Medicaments such as salicylates, ferrous compounds,Zoxazolamine and phenylbutazine, which tend to cause discomfort when incontact with the stomach and when oft times have to be taken every fourhours for therapeutic results, fall within the scope of this invention.

The medicament is coated upon the core pellet, or the core pellet can bemade of the medicament itself, and then treated with a series of afour-hour duration, with the wax-like textured coating. Another dosageof medicament may be applied at this stage over the medicatedwax-treated pellets, and another series of wax-like coatings may beapplied say for another four-hour duration.

This pellet will release active medicament at every fourhour interval.Still another series of wax-like coatings is further added to the pelletsurface to sustain activity for an additional four hours in theintestines. The last dosage of medicant is applied over this wax-likecoating, and the pellet is sealed with C.A.P.-acetone solution. Thepellets are then dried and placed into proper vehicles (tablets,capsules or the pellets, per se).

Upon ingestion the vehicle will release its pellets. The pellets Willpass through the stomach without any noticeable change and then enterthe intestinal tract.

In the intestinal area, the C.A.P.-acetone covering is dissolved and adosage of medicaments is released for absorption, exposing the outerseries of wax-like coatings which will slowly dissolve and expose thesecond layer or dosage of medicaments for absorption at the fourhoursustaining period.

Intestinal activity will then again slowly dissolve the inner layers ofwax-like materials and retard the release of the innermost layer ofmedicament or the medicated core itself for the next four-hour period.When the retardant wax-like coatings are dissolved, the medicament isavailable for absorption. ,7

This example illustrates the scope of the invention by allowing threedistinct dosages of medication to be incorporated into each individualpellet. 'Ihe medications being of a type incompatible with gastricactivity, by utilizing this invention we eliminate discomfort to thepatient and allow the individual to ingest one tablet, capsule or fixedamount of pellets, per se, instead of three individual dosage forms.

EXAMPLE 4 Utilizing the method as set forth in Example 1, larger dosesof medications may be incorporated into tablets, capsules or pellets,per se.

Where recommended doses of medication call for specific amounts in anyone hour (Isopropyl Arterenol Hydrochloride-5 mgm.), this example fallswithin the scope of the invention.

Normally, tablets containing the exact amount of medication are taken bythe patient in accordance with the physicians instructions and with therecommended dosage as stated.

Pellets containing overall larger dosages are fabricated in accordancewith the concept as set forth in this invention. These pellets arecoated with enough medicament to construct a tablet or capsule or fixedamount of pellets, per se, to total 40 mgm. of active medicament(Isopropyl Arterenol Hydrochloride).

Upon ingestion, the unprotected medically coated pellets, which compriseof the overall batch of treated pellets, will release their portion ofmedicant for absorption (4 mgm.) within the first hour. The remaining 7of the pellets (36 mgm.) pass through the stomach unchanged due to itsprotective gastric coating (C.A.P.- acetone coating) and upon enteringthe intestinal tract, said coating will dissolve.

The original portion of pellets which has not been treated with theretardant wax-like coatings exposes its medicament for absorption GA; of36 mgm.=4 mgm.) within the second hour.

The third hour after ingestion allows the original Ms portion of thepellets, which contains but one series of 7.5% wax-like coatingsustaining factor, to dissolve its coating in the intestines andreleases its medication for absorption A3 of 32 mgm.=4 mgm.).

The next hour of intestinal activity will enable the portion to releaseits medication (V; of 28 mgm.=4 mgm.).

Still further, the next hour of intestinal activity will allow the /6portion of the originally treated pellets to release its medication (Msof 24 mgm.=4 mgm.).

Intestinal activity continues and each hour of said activity will enableanother portion of pellets to release its medicant. The sixth hourreleases the portion (Vs of 20 mgm.=4 mgm.). The seventh hour exposesthe medicant of the original portion of pellets of 16 mgm.=4 mgm.). Theeighth hour exposes the medicament of the /3 portion of the originalpellets of 12 mgm.=4 mgm.). medicament of the /2 portion of the originalbatch to expose itself for absorption 0/: of 8 mgm.=4 mgm.), and thetenth hour will allow the remainder of the pellets (4- mgm.) to beabsorbed.

The scope of this invention enables larger doses of medicant to beincorporated into one dosage, from pellets made into a tablet, capsuleor the pellets, per se, in weighed, calculated amounts, and yet releasesin any one hour not more than the recommended dosage, as determined bycommon practice.

I claim:

1. A sustained release type pharamaceutical pellet comprising an innercore coated With a member of the group consisting of sucrose, celluloseacetate-phthalate, pharmaceutical glazes and vegetable gums and havingat least one surrounding layer of a medicament thereon, a coating uponeach medicament layer comprising a mixture of not less than about byweight of said coating of a glyceride of a long chain aliphaticcarboxylic acid, and minor amounts of at least one long chain fattyalcohol and of beeswax, the weight of each coating being between about5% and about 10% by weight of that portion of said The ninth hour willenable thepellet coated thereby, each such coating providingapproximately an hourly increment of sustainment.

2. A sustained release type pharmaceutical tablet comprising a mixtureof pellets as claimed in claim 1, said tablet having a sustainment timeof at least one hour.

3. A sustained release type pharmaceutical pellet comprising an innercore coated with a member of the group consisting of sucrose, celluloseacetate-phthalate, pharmaceutical glazes and vegetable gums and havingat least one surrounding layer of a medicament thereon, a coating uponeach medicament layer comprising a mixture of not less than about 95% byweight of said coating of a glyceride of a long chain aliphaticcarboxylic acid, and minor amounts of at least one long chain fattyalcohol and of beeswax, the weight of each coating being about 7.5% byweight of that portion of said pellet coated 10 thereby, each suchcoating providing approximately an hourly increment of sustainment.

References Cited in the file of this patent UNITED STATES PATENTS2,853,420 Lowey Sept. 23, 1958 2,881,085 Endicott et al Apr. 7, 19592,887,438 Cooper et al May 19, 1959 2,928,770 Bardani Mar. 15, 19602,954,323 Endicott et al Sept. 27, 1960 2,956,926 Grief Oct. 18, 1960OTHER REFERENCES Gross et a1.: Transformulation to Film Coating," inDrug and Cosmetic Industry (D.C.I.) 86 (2), pp. 170- 171, 264, 288-291,February 1960.

1. A SUSTAINED RELEASE TYPE PHARMACEUTICAL PELLET COMPRISING AN INNERCORE COATED WITH A MEMBER OF THE GROUP CONSISTING OF SUCROSE, CELLULOSEACETATE-PHTHALATE, PHARMACEUTICAL GLAZES AND VEGETABLE GUMS AND HAVINGAT LEAST ONE SURROUNDING LAYER OF A MEDICAMENT THEREON, A COATING UPONEACH MEDICAMENT LAYER COMPRISING A MIXTURE OF NOT LESS THAN ABOUT 95% BYWEIGHT OF SAID COATING OF A GLYCERIDE OF A LONG CHAIN ALIPHATICCARBOXYLIC ACID, AND MINOR AMOUNTS OF AT LEAST ONE LONG CHAIN FATTYALCOHOL AND OF BEESWAX, THE WEIGHT OF EACH COATING BEING BETWEEN ABOUT5% AND ABOUT 10% BY WEIGHT OF THAT PORTION OF SAID PELLET COATEDTHEREBY, EACH SUCH COATING PROVIDING APPROXIMATELY AN HOURLY INCREMENTOF SUSTAINMENT.